tbuckley/cabot-search huggingface dataset:
PB1788: A SCREENING OF DONATED CHEMICAL PROBES TO IDENTIFY NOVEL THERAPEUTIC OPTIONS FOR ACUTE MYELOID LEUKEMIA (AML) IN CHILDHOOD
Authors: Stephanie Laszig, Raj Bhayadia, Jan-Henning Klusmann, Stefan Knapp
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Despite intensive treatment regimens, the survival rate for children with acute myeloid leukemia (AML) has remained stagnant at around 70%. To improve the chances of survival for children with AML, novel therapeutic agents are urgently needed. Recently, targeted therapies and small molecules have emerged as promising alternative treatment options. The Structural Genomics Consortium (SGC), along with several pharmaceutical companies, has made multiple validated small molecules available for research. These so-called “donated chemical probes” (DCPs) can aid in identifying therapeutic targets and treatment options for various diseases. Aims: The goal of this study was to identify novel therapeutic targets and options for children with AML. We conducted a screening of donated chemical probes (DCPs) in AML cell lines and patient-derived cells from pediatric AML. Methods: In this study, we treated various AML cell lines with 105 small molecules from a donated chemical probe (DCP) library at concentrations ranging from 1nM to 10µM. To assess the effect of each compound on cell viability, we conducted a CellTiter-Glo assay after the treatment period. Analysis of dose-response curves and calculation of the area under the curve (AUC) identified several effective compounds in AML cell lines. We subsequently evaluated the most promising candidates from our initial screening in patient-derived AML-blasts, which identified certain groups of small molecules as potent anti-leukemic compounds. To further elucidate their effects in AML cells, we used various methods, including flow cytometric analysis of surface markers and cell cycle, analysis of cell death, and Western blotting. Results: From the 105 small molecules we tested, we identified inhibitors of Cdc2-like kinases (CLKs), among others, as promising compounds for our study. CLKs play a crucial role in splicing processes, and mutations in splicing factors or changes in their expression levels are linked to both solid and hematological malignancies. Based on our screening results, we investigated the potential of CLK inhibitors in pediatric AML. We found that these inhibitors reduced cell viability and induced apoptotic cell death in AML cells in a dose-dependent manner. Additionally, the tested compounds caused G1-phase arrest in AML cells. These findings suggest that interfering with alternative splicing through inhibition of CLKs could offer a novel therapeutic option for pediatric AML. Summary/Conclusion: Our screening of a donated chemical probe (DCP) library revealed the inhibition of CLKs as a highly promising therapeutic option for childhood AML. Keywords: Alternative splicing, Acute myeloid leukemia
PB2447: PREEMPTIVE TREATMENT WITH PD-1 ANTIBODY FOR ACUTE MYELOID LEUKEMIA/MYELODYSPLASTIC SYNDROME WITH POSITIVE MINIMAL RESIDUAL DISEASE AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Ling MA, Yuqian Sun, Xiaojun Huang
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Minimal residual disease (MRD) has been the strongest predictor for recurrence of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Preemptive therapy with donor lymphocyte infusion (DLI), interferon-α, targeted drugs is the effective strategy to reduce the recurrence after transplantation, however, this is not suitable for all patients. Studies had shown that the PD-1 pathway is an escape mechanism for tumor stem cells, but there are few data on the safety and efficacy of PD-1 inhibitors in patients with AML/MDS after transplantation. Aims: To evaluate the efficacy and safety of PD-1 antibody administered to patients with AML or myelodysplastic syndrome MDS with repeatedly positive MRD after allo-HSCT. Methods: We studied 6 patients with AML/MDS who underwent PD-1 antibody treatment for repeatedly positive MRD detected by multiparameter flow cytometry (FCM) or PCR after allo-HSCT between January 2022 and March 2022 at Peking University Institute of Hematology. PD-1 antibody (200-240mg for once every 2 to 3 weeks) single or combined with azacitidine (100mg for 5 to 7 days) was given until disease progression or unacceptable toxicity occurs. Results: 6 patients were recruited (AML 5, and MDS 1), with median age of 36 years (range, 26-38 years) and 50% males. 4 cases received combined treatment and 2 cases received monotherapy. Before PD-1 antibody treatment, 4 patients (66.7%) received interferon-α therapy, 6 patients (100%) received chemotherapy combined with DLI, and all patients had received two or more treatments. The median treatment with PD-1 antibody was 4 doses (rang, 1 to 7 doses). One patient died of seizure at 10 days after treatment and one died of severe chronic GVHD at 107 days after treatment. One patient developed grade 3-4 toxicity, including chronic GVHD, myelosuppression, infection, and hepatotoxicity and the remaining 3 cases had no grade >2 toxicities. 4 of 5 evaluable patients (80%) achieved negative MRD, and the median time to response was 25 days (rang, 16-56 days), the median duration of negative MRD was 86 days (26-211 days). 3 of the 4 patients had positive MRD again at 82 days, 90 days and 316 days after treatment, respectively. The median survival time of five patients after preemptive treatment of PD-1 antibody was 320 days (rang, 107-350 days). Summary/Conclusion: PD-1 antibody administration for AML/MDS patients with positive MRD after allo-HSCT could be a safe and effective strategy, but the effect was not lasting. Keywords: Minimal residual disease (MRD), Allogeneic hematopoietic stem cell transplant
PB1828: REALGAR (AS4S4), A TRADITIONAL CHINESE MEDICINE, INDUCES ACUTE PROMYELOCYTIC LEUKEMIA CELL DEATH VIA THE BCL-2/BAX/CYT-C/AIF SIGNALING PATHWAY IN VITRO
Authors: Zonghong LI, Siyuan Cui, Jinxin Wang, Shumin Ding, Ruirong Xu
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute promyelocytic leukemia (APL) is a specific subtype of acute myelogenous leukemia (AML) characterized by the proliferation of abnormal promyelocytes. Realgar, a Chinese medicine containing arsenic, can be taken orally. Traditional Chinese medicine physicians have employed realgar to treat APL for over a thousand years. Therefore, realgar may be a promising candidate for the treatment of APL. Nevertheless, the underlying mechanism behind realgar therapy is largely unclear. Aims: The present study aimed to investigate the effect of realgar on cell death in the APL cell line (NB4) in vitro and to elucidate the underlying mechanism. Methods: In this study, after APL cells were treated with different concentrations of realgar, the cell survival rate, apoptotic assay, morphological changes, ATP levels and cell cycle arrest were assessed. The expression of Bcl-2, Bax, Cytochrome C (Cyt-C) and apoptosis-inducing factor (AIF) at the mRNA and protein levels were also measured by immunofluorescence, quantitative PCR (qPCR) and Western blotting. Results: We found that realgar could significantly inhibit APL cell proliferation and cell death in a time- and dose-dependent manner. Realgar effectively decreased the ATP levels in APL cells. Realgar also induced APL cell cycle arrest at the S and G2/M phases. Following realgar treatment, the mRNA and protein levels of Bcl-2 were significantly downregulated, whereas the levels of Bax, Cyt-C, and AIF were significantly upregulated. Summary/Conclusion: In summary, realgar can induce APL cell death via the Bcl-2/Bax/Cyt-C/AIF signaling pathway, suggesting that realgar may be an effective therapeutic for APL. Graphical AbstractKeywords: APL, BCL2, Apoptosis, Bax
Carbon Monoxide Poisoning: From Microbes to Therapeutics
Authors: Matthew R. Dent, Jason J. Rose, Jesús Tejero, Mark T. Gladwin
Journal: Annual Review of Medicine (2023)

Carbon monoxide (CO) poisoning leads to 50,000–100,000 emergency room visits and 1,500–2,000 deaths each year in the United States alone. Even with treatment, survivors often suffer from long-term cardiac and neurocognitive deficits, highlighting a clear unmet medical need for novel therapeutic strategies that reduce morbidity and mortality associated with CO poisoning. This review examines the prevalence and impact of CO poisoning and pathophysiology in humans and highlights recent advances in therapeutic strategies that accelerate CO clearance and mitigate toxicity. We focus on recent developments of high-affinity molecules that take advantage of the uniquely strong interaction between CO and heme to selectively bind and sequester CO in preclinical models. These scavengers, which employ heme-binding scaffolds ranging from organic small molecules to hemoproteins derived from humans and potentially even microorganisms, show promise as field-deployable antidotes that may rapidly accelerate CO clearance and improve outcomes for survivors of acute CO poisoning.
Alzheimer’s disease and related tauopathies: disorders of disrupted neuronal identity
Authors: Bess Frost
Journal: Trends in Neurosciences (2023)

Postmitotic neurons require persistently active controls to maintain terminal differentiation. Unlike dividing cells, aberrant cell cycle activation in mature neurons causes apoptosis rather than transformation. In Alzheimer's disease (AD) and related tauopathies, evidence suggests that pathogenic forms of tau drive neurodegeneration via neuronal cell cycle re-entry. Multiple interconnected mechanisms linking tau to cell cycle activation have been identified, including, but not limited to, tau-induced overstabilization of the actin cytoskeleton, consequent changes to nuclear architecture, and disruption of heterochromatin-mediated gene silencing. Cancer- and development-associated pathways are upregulated in human and cellular models of tauopathy, and many tau-induced cellular phenotypes are also present in various cancers and progenitor/stem cells. In this review, I delve into mechanistic parallels between tauopathies, cancer, and development, and highlight the role of tau in cancer and in the developing brain. Based on these studies, I put forth a model by which pathogenic forms of tau disrupt the program that maintains terminal neuronal differentiation, driving cell cycle re-entry and consequent neuronal death. This framework presents tauopathies as conditions involving the profound toxic disruption of neuronal identity.
Next batter up! Targeting cancers with KRAS-G12D mutations
Authors: Mara N. Zeissig, Lauren M. Ashwood, Olga Kondrashova, Kate D. Sutherland
Journal: Trends in cancer (2023)

KRAS is the most frequently mutated oncogene in cancer. Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. In this Review, we discuss the genomics and biology of KRAS-G12D adenocarcinomas, including histological features, transcriptional landscape, the immune microenvironment, and how these factors influence response to therapy. Moreover, we explore potential therapeutic strategies using novel G12D inhibitors, leveraging knowledge gained from clinical trials using G12C inhibitors.
Towards a bidirectional decoloniality in academic global health: insights from settler colonialism and racial capitalism
Authors: Bram Wispelwey, Chidinma Osuagwu, David Mills, Tinashe Goronga, Michelle Morse
Journal: The Lancet Global Health (2023)

This Viewpoint considers the implications of incorporating two interdisciplinary and burgeoning fields of study, settler colonialism and racial capitalism, as prominent frameworks within academic global health. We describe these two modes of domination and their historical and ongoing roles in creating accumulated advantage for some groups and disadvantage for others, highlighting their relevance for decolonial health approaches. We argue that widespread epistemic and material injustice, long noted by marginalised communities, is more apparent and challengeable with the consistent application of these two frameworks. With examples from the USA, Brazil, and Zimbabwe, we describe the health effects of settler colonial erasure and racial capitalist exploitation, also revealing the rich legacies of resistance that highlight potential paths towards health equity. Because much of the global health knowledge production is constructed from unregenerate contexts of settler colonialism and racial capitalism and yet focused transnationally, we offer instead an approach of bidirectional decoloniality. Recognising the broader colonial world system at work, bidirectional decoloniality entails a truly global health community that confronts Global North settler colonialism and racial injustice as forcefully as the various colonialisms perpetrated in the Global South.
Not just surveys and indicators: narratives capture what really matters for health system strengthening
Authors: Dorothy Oluoch, Sassy Molyneux, Mwanamvua Boga, Justinah Maluni, Florence Murila, Caroline Jones, Sue Ziebland, Mike English, Lisa Hinton
Journal: The Lancet Global Health (2023)

Health system strengthening remains elusive and challenging. Health systems in many countries in sub-Saharan Africa are frequently characterised as weak, with inadequate management and accountability mechanisms, and poor human and financial resources. Putting patients and staff at the heart of health systems is an essential step towards strengthening them. As one of the three pillars of quality in health care, understanding patient experiences is key to moving towards people-centred care. Yet patient experiences are not a singular concept. Patient narratives can convey individual experiences of illness and health care, which complement and augment epidemiological and public health evidence. These narratives, gathered with rigorous, interview-based research and shared with digital tools (audio and video), can generate persuasive evidence. This evidence has important potential for influencing policy and practice, and for supporting people-centred care, but has not been tested systematically in low-income countries. In the Kenyan context of newborn health, work under way is generating evidence to show the transformative potential of patient narratives.
Intimate partner violence victimisation and its association with maternal parenting (the 2015 Pelotas [Brazil] Birth Cohort): a prospective cohort study
Authors: Carolina V N Coll, Aluisio J D Barros, Alan Stein, Karen Devries, Romina Buffarini, Lynne Murray, Adriane Arteche, Tiago N Munhoz, Mariângela F Silveira, Joseph Murray
Journal: The Lancet Global Health (2023)

BackgroundIntimate partner violence (IPV) is highly prevalent in low-income and middle-income countries and has been a major obstacle towards reaching global health targets for women and children. We aimed to investigate cross-sectional and longitudinal associations between IPV victimisation and maternal parenting practices of young children in a population-based birth cohort study in Brazil.MethodsThe 2015 Pelotas Birth Cohort is an ongoing, prospective cohort, including all hospital births occurring between Jan 1 and Dec 31, 2015, in the city of Pelotas, Brazil. When children were aged 4 years, mothers reported on emotional, physical, and sexual IPV victimisation in the past 12 months. Parenting outcomes were assessed through filming the mother and child in interactive tasks at age 4 years and maternal interviews at ages 4 years and 6–7 years. Interactive tasks were filmed at the Centre for Epidemiological Research facilities. Directly observed outcomes included negative (eg, coercive) and positive (eg, sensitivity and reciprocity) parenting interactions independently coded by a team of psychologists. Self-reported parenting was measured using the subscales on quality of parent–child relationship, positive encouragement, parental consistency, and coercive behaviour of the Parenting and Family Adjustment Scales questionnaire. Unadjusted and adjusted linear regression analyses were performed to assess the associations.FindingsOf the 4275 livebirths enrolled in the cohort, 3730 mother–child dyads were included in our analytical sample at age 4 years and 3292 at age 6–7 years. After adjusting for all potential confounders, emotional IPV and physical or sexual IPV were associated with the following self-reported parenting outcomes: poor parent–child relationship quality (emotional IPV: p=0·011), lower parental consistency (emotional IPV: p<0·001, physical or sexual IPV: p=0·0053), and more coercive behaviour (emotional IPV: p<0·001, physical or sexual IPV: p=0·0071) at age 4 years. Associations were not observed for self-reported positive encouragement and filmed parenting outcomes in fully adjusted models. Longitudinally, IPV at age 4 years predicted similar outcomes when children were aged 6–7 years.InterpretationIn this large cohort study, maternal IPV victimisation was consistently associated with poorer parent–child relationship, decreased parental consistency, and increased harsh parenting reported by mothers of young children. As well as initiatives to prevent IPV, parenting interventions focused on supporting the capacity of caregivers to provide nurturing care delivered at key stages early in the life course are crucial.FundingWellcome Trust, Bernard van Leer Foundation.TranslationFor the Portuguese translation of the abstract see Supplementary Materials section.
Health system resilience: a critical review and reconceptualisation
Authors: Sophie Witter, Steve Thomas, Stephanie M Topp, Edwine Barasa, Mickey Chopra, Daniel Cobos, Karl Blanchet, Gina Teddy, Rifat Atun, Alastair Ager
Journal: The Lancet Global Health (2023)

<h2>Summary</h2> This Viewpoint brings together insights from health system experts working in a range of settings. Our focus is on examining the state of the resilience field, including current thinking on definitions, conceptualisation, critiques, measurement, and capabilities. We highlight the analytical value of resilience, but also its risks, which include neglect of equity and of who is bearing the costs of resilience strategies. Resilience depends crucially on relationships between system actors and components, and—as amply shown during the COVID-19 pandemic—relationships with wider systems (eg, economic, political, and global governance structures). Resilience is therefore connected to power imbalances, which need to be addressed to enact the transformative strategies that are important in dealing with more persistent shocks and stressors, such as climate change. We discourage the framing of resilience as an outcome that can be measured; instead, we see it emerge from systemic resources and interactions, which have effects that can be measured. We propose a more complex categorisation of shocks than the common binary one of acute versus chronic, and outline some of the implications of this for resilience strategies. We encourage a shift in thinking from capacities towards capabilities—what actors could do in future with the necessary transformative strategies, which will need to encompass global, national, and local change. Finally, we highlight lessons emerging in relation to preparing for the next crisis, particularly in clarifying roles and avoiding fragmented governance.
Cardiopulmonary resuscitation in low-resource settings: a statement by the International Liaison Committee on Resuscitation, supported by the AFEM, EUSEM, IFEM, and IFRC
Authors: Sebastian Schnaubelt, Rakesh Garg, Huba Atiq, Noor Baig, Marta Bernardino, Blair Bigham, Samantha Dickson, Heike Geduld, Zehra’ Al-Hilali, Sanjaya Karki, Sa’ad Lahri, Ian Maconochie, Fernando Montealegre, Mahmoud Tageldin Mustafa, Susan Niermeyer, Justine Athieno Odakha, Jeffrey M Perlman, Koenraad G Monsieurs, Robert Greif, Firas Aldakak, Farhan Bhanji, Jan Breckwoldt, Adam Cheng, Andrea Cortegiani, Kathryn Eastwood, Barbara Farquharson, Judith Finn, Cristian Abelairas Gómez, Ming-Ju Hsieh, Kasper Glerup Lauridsen, Andrew Lockey, Sabine Nabecker, Kevin Nation, Alexander Olaussen, Taylor Sawyer, Chih-Wei Yang, Joyce Yeung
Journal: The Lancet Global Health (2023)

Most recommendations on cardiopulmonary resuscitation were developed from the perspective of high-resource settings with the aim of applying them in these settings. These so-called international guidelines are often not applicable in low-resource settings. Organisations including the International Liaison Committee on Resuscitation (ILCOR) have not sufficiently addressed this problem. We formed a collaborative group of experts from various settings including low-income, middle-income, and high-income countries, and conducted a prospective, multiphase consensus process to formulate this ILCOR Task Force statement. We highlight the discrepancy between current cardiopulmonary resuscitation guidelines and their applicability in low-resource settings. Successful existing initiatives such as the Helping Babies Breathe programme and the WHO Emergency Care Systems Framework are acknowledged. The concept of the chainmail of survival as an adaptive approach towards a framework of resuscitation, the potential enablers of and barriers to this framework, and gaps in the knowledge are discussed, focusing on low-resource settings. Action points are proposed, which might be expanded into future recommendations and suggestions, addressing a large diversity of addressees from caregivers to stakeholders. This statement serves as a stepping-stone to developing a truly global approach to guide resuscitation care and science, including in health-care systems worldwide.
Artificial intelligence and digital health in global eye health: opportunities and challenges
Authors: Ting Fang Tan, Arun J Thirunavukarasu, Liyuan Jin, Joshua Lim, Stanley Poh, Zhen Ling Teo, Marcus Ang, R V Paul Chan, Jasmine Ong, Angus Turner, Jonas Karlström, Tien Yin Wong, Jude Stern, Daniel Shu-Wei Ting
Journal: The Lancet Global Health (2023)
Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models
Authors: Alan C. Rupp, Abigail J. Tomlinson, Alison H. Affinati, Warren T. Yacawych, Allison M. Duensing, Cadence True, Sarah R. Lindsley, Melissa A. Kirigiti, Alexander MacKenzie, Joseph Polex-Wolf, Chien Li, Lotte Bjerre Knudsen, Randy J. Seeley, David P. Olson, Paul Kievit, Martin G. Myers
Journal: Journal of Clinical Investigation (2023)

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A previously unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-sequencing of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.